M. leprae Binding to Target Cells
Pathogenic bacteria are adapted to exploit a variety of host cell functions, and host cell receptors usually serve as the initial target for bacterial interaction with a specific cell type (Finlay and Cossart, Science 276:718, 1997; Falkow, Cell 65:1099, 1991). However, not much is known about the bacterial receptors in the nervous system and how bacteria interfere with these neuronal cell receptor-associated functions. Mycobacterium leprae, the causative organism of leprosy, is an intracellular pathogen which invades the Schwann cell of the peripheral nervous system (Falkow, supra). The neural tropism of this disease has been recognized for almost 150 years but has remained unexplained. At present, it is estimated that 2-3 million leprosy patients in the world are physically disabled as a result of damage to peripheral nerves and the attendant sensorimotor loss (Job, Int. J. Lpr. 57:532, 1989; Noordeen et al., Bull. World Health Org. 70:7, 1992).
During infection, M. leprae cause significant damage to peripheral nerves leaving patients with disabilities and deformities (Job, supra). Schwann cells are unable to destroy the pathogens that reside intracellularly, and access of therapeutic agents to this site is limited owing to the blood-nerve barrier. Although antibiotic therapy and long-term multi-drug treatment are effective bacteriological cures for leprosy, they do not reverse the nerve function loss in these patients (WHO Weekly Epidemiological Record. Sep. 20, p. 269, 1995). Understanding the mechanisms of M. leprae-Schwann cell interaction may yield new therapeutic strategies for the prevention of nerve damage.
In the endoneurium of peripheral nerves, all Schwann cells are characterized by a basal lamina covering. Since M. leprae must interact with the basal lamina in order to reach the Schwann cell, tropism to this site and perhaps cellular entry might involve the components of Schwann cell basal lamina. Schwann cell basal lamina is comprised of laminin, type IV collagen, entactin/nidogen, and heparin sulfate proteoglycans (Combrooks et al., Proc. Natl. Acad. Sci. USA 80:3850, 1983; Jaakkola et al., J. Neurocytol. 22:215, 1989; Sanes et al., J. Cell Biol. 111:1685, 1990). Although there is evidence that M. leprae binds to fibronectin (Schorey et al., Infect. Immun. 63:2652, 1995), this binding may not be relevant for M. leprae interaction with Schwann cells in vivo, since both fibronectin mRNA and protein are absent in Schwann cell basal lamina in situ and in primary cultures (Combrooks et al., 1983, supra; Jaakkola et al., 1989, supra). Conversely, considering the continuous presence of laminin around the Schwann cell-axon unit in vivo, laminin appeared to be a candidate as an initial target for M. leprae.
Laminins (LNs) are glycoproteins comprised of three polypeptide chains, .alpha., .beta., and .gamma.. The .alpha. chain distinguishes itself by having an extra domain at the C-terminus, i.e., the G domain (Burgeson, et al., Matrix Biol. 14:209, 1994; Timpl and Brown, Matrix Biol. 14:275, 1994). At least 10 genetically distinct LN chains have been identified (.alpha.1, .alpha.2, .alpha.3, .alpha.4, .alpha.5, .beta.1, .beta.2, .beta.3, .gamma.1, and .gamma.2), which assemble into 11 different LN isoforms (LN-1 to -11), each with restricted tissue distribution (reviewed in Timpl and Brown, supra Engvall and Wewer, J. Cell Biochem. 61:493, 1996). In the Schwann cell basal lamina, the predominant LN variant is LN-2 (merosin), which comprises tissue-specific .alpha.2 heavy chain together with the .beta.1 and .gamma.1 light chains (Leivo and Engvall, Proc. Natl. Acad. Sci. USA 85:1544, 1988; Engvall et al., Cell Regul. 1:731, 1990. LN-2 not only forms a major basement membrane network, but also enables a variety of functions of neural cells (Engvall et al., Exp. Cell Res. 198:115-123 1992; Yurchenco et al., J. Biol. Chem. 268:8356, 1992; Anton et al., Dev. Biol. 164:133, 1994). The major cell receptors for LN are the members of the integrin superfamily (Mercurio, Trends Cell Biol. 5:419, 1995). Several integrin receptors bind to LN, and .alpha..sub.6.beta..sub.1 and .alpha..sub.6.beta..sub.4 integrins, particularly the .beta..sub.4 subunit, appear to be involved in the Schwann cell interaction with LN (Einheber et al., J. Cell Biol. 123:1223, 1993; Jaakkola et al., supra; Feltri et al., Development 120:1287, 1994; Niessen et al., Development 120:1287, 1994).
The neural tropism of M. leprae involves the bacterial binding to the G domain of the LN-.alpha.2 chain, which serves as a bridge between M. leprae and the native LN receptors on Schwann cells (Rambukkana et al., Cell 88:811, 1997). The LN-.alpha.2G domain serves as both the bacterial and human cell binding site, which is possibly mediated by the .beta..sub.4 integrin subunit as a host-cell receptor for LN-.alpha.2G-mediated M. leprae cell interaction. However, the actual host cell receptor had not been identified. In order to provide more effective treatments for leprosy, and to better understand this disease and other musculo- and neuro-degenerative diseases involving laminins, it is necessary to determine the host cell receptor.